Phase 3 KEYNOTE-775 Trial in Advanced Endometrial Cancer

Vicky Makker, MD: I’m going to discuss the efficacy data and review the primary and secondary end points from Study 309, or KEYNOTE-775. This is an open-label, randomized, phase 3 confirmatory trial of oral tyrosine kinase inhibitor lenvatinib and anti–PD-1 monoclonal antibody pembrolizumab vs treatment of physician’s choice [TPC] in advanced endometrial cancers following at least 1 prior platinum-based regimen. The key eligibility criteria for this study included advanced metastatic or recurrent endometrial cancers with measurable disease by RECIST 1.1 guidelines per blinded independent central review. Patients in this study had to have 1, but were allowed 2, prior platinum-based lines of therapy, as long as 1 was administered in the adjuvant or neoadjuvant setting. There was no restriction on prior hormonal therapy in this study. Patients were stratified by their MMR [mismatch repair] status. The MMR-proficient [pMMR] cohort were further stratified by region, ECOG [performance] status, and prior history of pelvic radiation.

Eligible patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously [IV] every 3 weeks vs treatment of physician’s choice, where the options were doxorubicin 60 mg/m2IV every 3 weeks or paclitaxel 80 mg/m2, 3 weeks on, 1 week off. Pembrolizumab in this study could be administered for up to a maximum of 35 doses, with lenvatinib continuing beyond that point as long as the patient was clinically benefiting. The maximum lifetime dose of doxorubicin allowed on this study was 500 mg/m2. The primary end points of the study were progression-free survival [PFS] by blinded independent central review and overall survival [OS]. Secondary end points included objective response rate, quality of life analysis, as well as safety. The key exploratory end point on this study was duration of response.

In this study, 827 patients were randomized between the 2 arms. The arms were balanced with regard to patient age, prior radiation therapy, ECOG status, and race distribution. Approximately 85% of patients in both arms were MMR-proficient. Endometrioid adenocarcinomas were the most common histology, as expected, and represented approximately 60% of cases in both the arms. Serous histology was the most common nonendometrioid histology at just over 25%, followed by clear cell and mixed histologic subtypes. Their proportions were relatively balanced between the 2 treatment arms. Seventy-nine percent of patients in the lenvatinib-pembrolizumab arm and 76% of patients in the TPC arm had 1 prior platinum-based therapy. The median PFS in the study for the pMMR cohort was 6.6 months vs 3.8 months for lenvatinib-pembrolizumab vs TPC, with a hazard ratio of 0.6. In all-comers, which included the MMR-deficient patients, the median PFS was 7.2 months vs 3.8 months for lenvatinib-pembrolizumab vs TPC, with a hazard ratio of 0.56. PFS was significantly longer for lenvatinib-pembrolizumab vs TPC regardless of MMR status.

Despite informal crossover when lenvatinib and pembrolizumab became approved in many countries, with a median follow-up of 11.4 months, lenvatinib-pembrolizumab significantly prolonged overall survival in pMMR and all-comers participants. Median overall survival for the pMMR cohort was 17.4 months vs 12 months for lenvatinib-pembrolizumab vs TPC, with a hazard ratio of 0.68. Median OS for all-comers was 18.3 months vs 11.4 months for lenvatinib-pembrolizumab vs TPC, with a hazard ratio of 0.62. Lenvatinib-pembrolizumab demonstrated an improvement in PFS and OS. There was a benefit in PFS and OS across all subgroups that were analyzed, including MMR status, histology, and prior lines of therapy in all-comers participants vs treatment of physician’s choice.

The objective response rate in this study was at least doubled with lenvatinib-pembrolizumab vs TPC in pMMR and all-comers participants. In the pMMR cohort, the objective response rate was 30% vs 15%. In the all-comers cohort, it was 32% vs 15% for lenvatinib-pembrolizumab vs TPC. The complete response and partial response rates were also approximately doubled for lenvatinib-pembrolizumab vs TPC. It’s also important to note that responses with lenvatinib-pembrolizumab were rapid and durable in both the pMMR and all-comers participants. The median time to response in the pMMR cohort was 2.1 months vs 3.5 months for lenvatinib-pembrolizumab vs TPC. In all-comers, the median time to response was 2.1 months for both arms. The median duration of response in the pMMR cohort was 9.2 months vs 5.7 months for lenvatinib-pembrolizumab vs TPC. And in all-comers, the median duration of response was 14.4 months vs 5.7 months for lenvatinib-pembrolizumab vs TPC.

Transcript Edited for Clarity